Discussion
Development of gastric MALT lymphoma appears to arise from two distinct
pathways both involving dysregulation of nuclear factor kappa light
chain enhancer of activated B-cells (NF-kB) activity.7There is a B-Cell receptor (BCR) dependent NF-kB activation pathway and
BCR-independent NF-kB activation pathway.7,8 BCR
dependent NF-kB activation relies on persistent antigen stimulation
which elicits inflammation and accelerated lymphoid proliferation
through a polyclonal B-cell response.7,9,10 This
pathway is also recognized as an anti-microbial responsive lymphoid
proliferation as when the stimulating antigen is removed, the
inflammation and lymphoid proliferation resolves.11The above mechanism is further supported by the effectiveness of
eradication therapy in the treatment of H. pylori associated MALT
lymphoma. Current literature suggests regression in up to 83% ofH. pylori associated MALT lymphoma cases when given triple or
quadruple therapy.12,13
Though uncommon, there are reports showing H. pylori negative
MALT lymphoma similar to our case presented above. The predominating
theory suggests a BCR-independent NF-kB activation pathway. Though there
is a clear theory describing the pathway for lymphoid proliferation inH. pylori negative patients, the exact mechanism is yet to be
determined and is likely multifactorial. One known etiology is a
pseudo-negative H. pylori associated MALT lymphoma. In these
patients, H. pylori testing is negative due to previous use of
antibiotics, bismuth, proton pump inhibitors (PPIs), or a combination of
the three despite active infection with H.
pylori .14 Some studies indicate t certain chromosomal
translocations or tumor suppression gene mutations can cause
constitutive lymphoid proliferation independent of a stimulating
antigen.15 Multiple publications demonstrate a high
incidence of translocation (11;18)(Q21;Q21) in H. pylori negative
MALT lymphomas.7,16-18 These translocations cause a
fusion of the N-terminus of the API2 gene to the C-terminus of the MALT1
gene and generates a functional API2–MALT1 fusion product which can
constitutively activate the NF-kB pathway.19
Presence of the t(11;18)(q21:q21) is seen in up to 30% of all gastric
MALT lymphomas and are demonstrated in up to 68% that are at stage IIE
or above.20 Unfortunately, the current available data
has not closely evaluated the incidence of these translocations in
patients with H. pylori negative gastric MALT lymphoma, though
there are multiple studies that show expression of these translocations
in up to 88% of these patients.7,16-20 Regardless,
the presence of t(11;18)(q21:q21) can help guide therapy as they are
only seen in approximately 3% of gastric MALT lymphomas that do respond
to traditional H. pylori eradication therapy.20Further studies noted that the presence of t(11;18)(q21:q21) predicted
poor response to alkylating agents (chlorambucil or cyclophosphamide)
but was unable to predict the response to
rituximab.21,22
Treatment of patients with H. pylori negative MALT lymphoma is
complicated and differs depending upon the patient’s comorbidities,
staging, and the presence or absence of translocations. Current
literature suggests using radiation therapy for patients with early
stage (Lugano I/II) gastric MALT lymphoma without evidence of H.
pylori infection and reported clinical remission rates in up to 100%
of patients.23,24 If radiation therapy fails or the
patient is found to be at an advanced stage, treatment with
immunotherapy (Rituxumab) can be trialed and has shown complete response
in up to 46% of patients.22,25 Prior to discovery the
of H. pylori , targeted gastric resection was used to great
therapeutic effect and long term survival.22,26However, more recent studies suggest that organ conserving therapy
presents no long-term disadvantages but spares the patient from
permanent nutritional and metabolic derangements.27For these reasons, surgical treatment of gastric MALT lymphoma is rarely
pursued.
In the case above, testing for t(11;18)(q21:q21) was negative. Rituximab
was preferred over radiation therapy in our patient with history of
systemic sclerosis but was ineffective.. She has shown endoscopic and
histologic improvement with radiation therapy with 3 month repeat follow
up endoscopy pending.
In conclusion, H. pylori negative gastric lymphoma of MALT type
is an uncommon presentation of non-Hodgkin lymphoma. Though the
mechanism appears well researched, the specific etiology remains
controversial. In patients with gastric lymphoma of MALT type, it is
important to rule out H. pylori infection. If negative, further
evaluation of the t(11;18)(q21:q21) can help further guide therapy and
predict patient outcomes. Lastly, MALT lymphoma in patients that have
undergone Roux-en-Y gastric bypass is uncommon with less than 40 cases
in the reported literature. Thus diagnosis can be delayed due to
mimicking symptoms typically attributed to the bypass. Evaluation, not
only of the gastric pouch, but also the gastric remnant should be
performed in all at risk patients as gastric MALT lymphoma can occur in
both locations despite post-operative anatomical separation.
The authors confirm contribution to the paper as follows:
Study conception and design: Zachary R Eagle
MD1; Francis Essien DO1; Kimberly
Zibert DO2; Charles Miller MD2; Rina
Eden DO3; Ross Pinson MD1,4
Data collection Zachary R Eagle MD1; Rina Eden
DO3; Ross Pinson MD1,4
Analysis and interpretation of results: Zachary R Eagle
MD1; Kimberly Zibert DO2; Charles
Miller MD2; Rina Eden DO3; Ross
Pinson MD1,4
Draft manuscript preparation: Zachary R Eagle
MD1; Francis Essien DO1; Ross Pinson
MD1,4
All authors discussed the results and contributed to the final
manuscript.
Data sharing is not applicable to this article as no new data were
created or analyzed in this study.